Thiazolecarboxamide sulfonylurea hypoglycemic agents

ABSTRACT

Several novel benzenesulfonylurea compounds derived from 4methyl-5-thiazolecarboxylic acid have been prepared by reacting 4-(2-(4-methyl-5-thiazolecarboxamido)ethyl)benzenesulfonamide with an appropriate organic isocyanate or a trisubstituted urea equivalent thereof. The sulfonylureas so obtained are useful in therapy as oral hypoglycemic agents. 1-Cyclohexyl-3-(4-(2-(4methyl-5 -thiazolecarboxamido)ethyl)benzenesulfonyl)urea represents a preferred embodiment.

mite States atent llfluhlla et al.

THIIAZULECARBOXAMIDE SULFONYLUREA HYPOGLYCEMIC AGENTS Inventors: Donald E. Kuhla, Gales Ferry;

Reinhard Sarges, Mystic; Hans E. Wiedermann, Niantic, all of Conn.

Assignee: Pfizer Inc., New York, NY.

Filed: Mar. 7, 1973 Appl. No.: 338,965

US. Cl. 260/302 R, 424/78, 424/80,

. 424/270 Int. Cl C07d 91/32 Field of Search 260/302 R Primary Examiner-Rich'ard J. Gallagher Attorney, Agent, or FirmConnolly and Hutz [57] ABSTRACT Several novel benzenesulfonylurea compounds derived from 4-methyl-5-thiazolecarb0xylic acid have been prepared by reacting 4-[2-(4-methyl-5- thiazolecarboxamido)ethyl]benzenesulfonamide with an appropriate organic isocyanate or a trisubstituted urea equivalent thereof. The sulfonylureas so obtained are useful in therapy as oral hypoglycemic agents. 1- Cyclohexyl-3-{4-[2-(4-methyl-5- thiazolecarboxamido)ethyl]benzenesulfonyl} urea represents a preferred embodiment.

4 Claims, N0 Drawings THIAZOLECARBOXAMIDE SULFONYLUREA HYPOGLYCEMIC AGENTS BACKGROUND OF THE INVENTION This invention relates to new and useful sulfonylurea derivatives, which are effective in reducing blood sugar levels to a remarkably highdegree. More particularly, it is concerned with certain benzenesulfonylureas and their base salts with pharmacologically acceptable cations, which are useful in therapy as oral hypoglycemic agents for the treatment of diabetes.

In the past, various attempts have been made by numerous investigators in the field of organic medicinal chemistry to obtain new and better oral hypoglycemic agents. For the most part, these efforts have principally involved thesynthesis and testing of various new and heretofore unavailable organic compounds, particularly in the area of the sulfonylureas and the various biguanidine derivatives. However, in the search for still newer and more improved oral hypoglycemic agents, far less is known about the activity of various substituted carboxamidobenzenesulfonylureas such as those which are derived from certain heterocyclic monocarboxylic acids. For instance, French Pat. No. 8220M discloses several acylamino-derived benzenesulfonylureas which contain an isothiazole ring and are reported to be active as hypoglycemic agents, but none of these aforementioned compounds presently possess any known clinical advantages over either chlorpropamide or tolbutamide when used in the treatment of diabetes.

SUMMARY or THE INVENTION In accordance with the present invention, it has now been rather surprisingly found that certain novel benzenesulfonylureas derived from 4-methyl-5- thiazolecarboxylic acid are extremely useful when employed as oral hypoglycemic agents for the multiple daily dosing of diabetic subjects. The novel sulfonylurea compounds of this invention are all selected from the group consisting of benzenesulfonylureas ofthe formula:

and the base salts thereof with 'pharmacologically acceptable cations, wherein R is bicyclo[ 2.2.l ]hept--en- Z-yI-endo-methyl or cycloalkyl having from five to seven carbon atoms. Typical member compounds specifically embraced by this invention include l- (bicyclo[2.2.l ]hept-S-en-2-yl-endomethyl)-3-{4-[2- (4-methyl-5-thiazdecarboxamido)ethylIbenzenesulfonyl urea, l-cyclopentyl-3- 4-[2-(4-methyl-5- thiazolecarboxamido)ethyllbenzenesulfonyl} urea, 1- cyclohexyl-3-{4-[2-(4-methyl-5- thiazolecarboxamido)ethyl]-benzenesulfonyl}urea and l-cycloheptyl-3-{4-[2-(4-methyl-5- thiazolecarboxamido)ethyl]benzenesulfonyl}urea, and their corresponding sodium salts. These particular compounds are all highly potent as regards their hypoglycemic activity and therefore are extremely useful in lowering blood sugar levels when given by the oral route of administration. Moreover, these novel agents all possess an ultra-short half-life and hence, give purposes at hand.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the process employed for preparing the novel compounds of this invention, 4-[2-(4- methyl-5-thiazolecarboxamido)ethyl]benzenesulfonamide is reacted with an organic isocyanate reagent of the formula RNCO wherein R corresponds to the previously defined l-substituent on the urea moiety of the desired final product. In this, way, the corresponding 4-[2-(4-methyl-5-thiazolecarboxamido)ethyl]ben zenesulfonylurea compound is formed having the requisite structural formula previously indicated. This particular reaction is normally conducted in a basic solvent medium, most desirably employing an aprotic organic solvent such as tetrahydrofuran, diinethylsulfoxide or dimethylformamide and preferably using a slight excess in moles of a base, like triethylamine or sodium hydride (in mineral oil), which may then be ad mixed with the solvent. Many of the aforesaid isocyanate reagents (RNCO) are either known compounds or else they can easily beprepared, using methods wellknown to those skilled in the art, starting from readily available materials. In practice, it is usually preferable to employ at least about a molar equivalent of the isocyanate reagent in the aforesaid reaction of the present invention, with best results often being achieved by using a slight excess of-same. Although any temperature below that of reflux may be used in order to effect the reaction, it is normally found most convenient in practice to employ elevated temperatures so to shorten the required reaction time, which may range anywhere from several minutes up to about 24 hours depending, of course, upon the particular benzenesulfonylurea actually being prepared. Upon completion of the reaction, the product is easily recovered from the spent re action mixture in a conventional manner, e.g., by pouring the mixture into an excess of ice-water-containing a slight excess of acid, such as hydrochloric acid, whereby the desired benzenesulfonylurea readily precipitates from solution and is subsequently collected by such means as suction filtration and the like.

Another method for preparing the novel compounds of this invention involves reacting 4-[2-(4-methyl-5- thiazolecarboxamido)-ethyl]benzenesulfonamide in the form of an alkali metal or alkaline-earth methal salt (either employed as such or else formed in situ) with an appropriate l,l,3-trisubstituted urea of the formula (R'hNCONHR, wherein R is an aryl group such as phenyl, p-chlorophenyl, p-bromphenyl, p-nitrophenyl, p-acetylaminophenyl, p-tolyl, p-anisyl, a-naphthyl, B-naphthyl and the like. This reaction is preferably carried out in the presence of an inert polar organic solvent medium. Typical organic solvents for use in this connection include the N,N-dialkyl lower alkanoamides like dimethylformamide, dimethylacetamide, diethylformamide and diethylacetamide, as well as lower dialkyl sulfoxides such as dimethyl sulfoxide; diethyl sulfoxide and di-n-propyl sulfoxide, etc. It is desirable that the aforesaid solvent for this reaction be present in sufficient amount to dissolve each'of the previously mentioned starting materials. In general, the reaction is conducted at a temperature that is in the range of from about 20C. up to about C. for a period of about a to about 1'0 hours. The relative amounts of reagents employed are such that the molar ratio of said smoother control of blood glucose levels when used benzenesulfonamide to the l,l-diaryl-3- (monosubstituted)urea is most desirably in the range of from about 1:1 to about 1:2, respectively. Recovery of the desired product from the reaction mixture is then achieved by first diluting the reaction solution with water and thereafter adjusting if necessary the pH of the resulting solution to a value of at least about 8.0, followed by thorough extraction of the basis aqueous solution with any water-immiscible organic solvent in order to remove the diarylamine byproduct of formula (R) NH as well as minor amounts of unreacted or excess starting material that might sitll possibly be present. isolation of the desired benzenesulfonylurea from the basic aqueous layer is then finally accomplished by adding a sufficient amount of a dilute aquoeus acid to the aforesaid basic solution to cause precipitation of the desired sulfonylurea therefrom.

The major starting materials required for this reaction, viz., 4-[2-(4-methyl-5- thiazolecarboxamido)ethyl]benzenesulfonamide and the l,l-diaryl-3-(monosubstituted)ureas, are readily prepared by those skilled in the art in accordance with the conventional methods of organic chemistry. For instance, 4-[2-(4-methyl-5-thiazolecarboxamido)ethyl]- benzenesulfonamide, which is also the same compound used as starting material in the previously described isocyanate method, is suitably obtained by using classical methods of organic synthesis starting from the known 4-(2-aminoethyl)benzenesulfonamide and proceeding in accordance with the procedure described in the experimental section of this specification in some detail (e.g., see Preparation A in this regard). The 1,1- diaryl-3-(monosubstituted)ureas, on the other hand, are all readily prepared from common organic reagents by employing standard procedures well known in the art. For example, the desired 1,1 ,3-trisubstituted urea may simply be obtained by treating the corresponding disubstituted carbamyl chloride [(R) NCOCI] with the appropriate amine (RNH in accordance with the general reaction procedure described by J. F. L. Reudler in Recueil des Travaux Chimigues des Pays-Bas., Vol. 33, p. 64 (1914 The chemical bases which are used as reagents in this invention to prepare the aforementioned pharmaceutically acceptable base salts are those which form nontoxic salts with the herein described acidic benzenesulfonylureas, such as l-cyclohexyl-3-{4-[2-(4-methyl-5- thiazolecarboxamido)ethyl]ben2enesulfonyl} urea, for example. These particular non-toxic base salts are of such a nature that their cations are deemed to be essentially non-toxic in character over the wide range of dosage administered. Examples of such cations include those of sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by simply treating the aforementioned benzenesulfonylureas with an aqueous solution of the desired pharmacologically acceptable base, i.e., those oxides, hydroxides, or carbonates which contain pharmacologically acceptable cations, and then evaporating the resulting solution to dryness while preferably being placed under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the said acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting aforesaid solution in the same manner as before. In either case, stoichiometric amounts of reagents must be employed in order to ensure completeness of reaction and consequent maximum production of yields with respect to the desired salt product.

As previously indicated, the benzenesulfonylurea compounds of this invention are all readily adapted to therapeutic use as oral hypoglycemic agents, in view of their ability to lower the blood sugar levels of diabetic and non-diabetic subjects to a statistically significant degree. For instance, l-cyclohexyl-3- {4-[2-(4-methyl-5-thiazolecarboxamido)ethyl]benzenesulfonyl}urea (as the sodium salt), a typical and preferred agent of the present invention, has been found to consistently lower blood sugar levels in the normal fasted rat to a statistically significant degree when given by either the oral or the intraperitoneal route of administration at dose levels ranging in either case from 0.5 mg./kg. to 5.0 mg./kg., respectively, without showing any substantial signs of toxic side effects. The other compounds of this invention also cause similar results. Furthermore, all the herein described compounds of this invention can be administered for the present purposes at hand without causing any significant untoward pharmacological side reactions to occur in the subject to whom they are so administered. in general, these compoupnds are ordinarily administered at dosage levels ranging from about 0.05 mg. to about 1.0 mg. per kg. of body weight per day, although variations will necessarily occur depending upon the condition and individual response of the subject being treated and the particular type of oral formulation chosen.

In connection with the use of the benzenesulfonylurea compounds of this invention for the treatment ofdiabetic subjects, it is to be noted that they may be administered either alone or in combination with pharmaceutically acceptable carriers and that such administration can be carried out in both single and multiple dosages. More particularly, the novel compounds of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, aqueous suspensions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical compositions can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for just such a purpose. In general, thetherapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 0.5 to about percent by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.

For purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and diealcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hardfilled gelatin capsules; preferred materials in this connection would also include the high molecular weight polyethylene glycols. When aqueous suspensions and- /or elixirs are desired for oral administration, the essential active ingredient therein may be combined with riod of approximately 16 hours with constant agitation being maintained throughout the entire step. At this point, the spent mixture was poured into 50 ml. of ice water and subsequently acidified with a few drops of S 3N aqueous hydrochloric acid. The resulting creamcolored precipitate was then recovered by means of suction filtration, washed well with cold water and thereafter crystallized from acetonitrile (after treatment with activated carbon) to yie ld 1.8 g. (73%) of ime 4 [2-(4-methyl-5-thiazolecarboxamido)ethyl]- benzenesulfonamide, mp. 18 2] 8 3C.

Anal. Found:

(1937). The latter method measures directly the amount of glucose in the blood at any given time and from this, the maximum percent decrease in blood sugar can be readily calculated and reported as hypoglycemic activity per se. in this way, the present benzenesulfonylurea compounds are shown to markedly reduce the blood sugar levels of non-anesthetized rats when administered to them at dose levels as low as 0.5 mg./kg.

Preparation A To a suspension of 0.715 g. (0.005 mole) of 4- methyl-5-thiazolecarboxylic acid [prepared according to the procedure of J DAmico et al., Journal 0f 0r: ganic Chemistry, Vol. 25, p. 1336 (1960)] in 7.0 ml. of carbon tetrachloride, there were added 7.0 ml. of thionyl chloride which had also been dissolved in 7.0 ml. of carbon tetrachloride. The resulting mixture was then refluxed on a steam bath for a period of one hour, at which point no further evolution of hydrogen chloride and sulfur dioxide gas could be detected. The homogeneous reaction mixture so obtained was then refluxed for an additional period of ten minutes, cooled to ambient temperatures and ultimately evaporated to near dryness while under reduced pressure to yield a residue substantially free of solvent and excess thionyl chloride. The latter material (i.e., the crude product) was thereafter dissolved in 20 ml. of benzene and again evaporated to near dryness while under reduced pressure. This particular purification step was repeated twice in order to remove the last traces of residual hydrogen chloride and thionyl chloride from the desired product. In this way. there was eventually obtained a quantitative yield of substantially pure 4-methyl-5- Preparation B 20 A 500 ml. three-necked, round-bottomed flask was charged with 14.6 g. (0.119 mole) of endo-2- aminomethylbicyclo[2 .2.1lhept 5-ene [P. Wilder et al., Journal of Organic Chemistry, Vol. 30, p. 3078 (1965)],18.0 g. (0.178 mole) oftriethylamine and 100 m1. of tetrahydrofuran. The mixture was then rapidly cooled and stirred in an ice bath, while a solution consisting of 27.4 g. (0.119 mole) of N,N- diphenylcarbamoyl chloride dissolved in 100 ml. oftet rahydrofuran was slowly added thereto in a dropwise manner. After the addition was complete, the reaction mixture was stirred at room temperature (-25C.) for a period of one hour and the resulting solution was then concentrated in vacuo (to approximately one-third of its original volume) to remove most of the tetrahydrofuran. On cooling, there was obtained a crystalline precipitate, which was subsequently collected by means of suction filtration and thereafter suspended in 250 m1. of 1N aqueous hydrochloric acid. Extraction of the latter aqueous solution with three-200 ml. portions ov chloroform, followed by drying of the combined organic extracts then gave a clear organic solution upon filtration. After evaporating the clear filtrate to near dryness while under reduced pressure, there was ultimately obtained a heavy viscous oil, which subsequently crystallized on trituration with n-hexane. Re-

crystallization of the latter solid material from diethyl ether/n-hexane then gave pure 1,1-diphenyl-3- (bicyclo[2.2.l Ihept-S-en-2-yl-endo-methyl)-urea, m.p. l29-l30C. The analytical sample was a crystalline white solid.

Anal. Calcd. for C H N O: C, 79.22; H. 6.96 N, 8.80. Found: C, 79.19; H, 7.05; N, 8.93.

EXAMPLE 1 thiazolecarboxylic acid chloride, which was used in the next reaction step without any further purification being necessary.

To a mixture of 1.18 g. (0.005 mole) of 4-(2- aminoethyl)-benzenesulfonamide hydrochloride [E. Miller et al., Journal of the American Chemical Society, Vol. 62, p. 2099 (1 940)] and 1.4rnl. (0 0l0rnole) of triethylamine in 51 ml. of dry tetrahydrofuran, there was added 805 mg. (0.005 mole) of 4-methy1-5- thiazolecarboxylic acid chloride dissolved in 15 ml. of

tetrahydrofuran. The addition caused a slight exothermic reaction to occur, after which the reaction mixture was allowed to stand at ambient temperatures for a pe- To a well-stirred solution (cooled in an ice bath) consisting of 651 mg. (0.002 mole) of 4-[2(4-methyl-5- thiazolecarboxamido)-ethyl]benzenesulfonamide dissolved in 5.0 m1. of dry N,N-dimethylformamide, there resulting mixture was then stirred at ambient temperatures for a period of approximately 2 hours, at which point thin-layer chromatography (TLC) analysis of an, aliquot portion showedessentially complete conversion. After pouring the mixture into 50 ml. of anhydrous diethyl ether, the sodium salt of the product precipitated as a white solid and was subsequently collected by means of suction filtration. The filter cake was washed well with diethyl ether and then dissolved in ml. of water. Upon acidification with 3N hydrochloric acid and extraction into chloroform, followed by decolorization with charcoal and drying over anhydrous magnesium sulfate, there was ultimately obtained a clear chloroform solution of the desired final product. Evaporation of the latter solution to near dryness while under reduced pressure then gave 704 mg. of pure 1- cyclohexy1-3-{4-[-(4-methyl-5-thiazolecarboxamido)- ethyl]benzenesulfonyl}urea as a colorless oil, which subsequently crystallized from acetonitrile in the form of white needles melting at 199-200C. The yield of pure crystalline material amounted to 506 mg. (56%).

8 EXAMPLE v EXAMPLE VI A dry solid pharmaceutical composition is prepared by blending the following materials together in the proportions by weight specified below:

Anal. Calcd. for C-mHmN O S2: C, 53.31: H, 5.81: N. 12.43. Found: C, 53.53; H, 5.94; N, 12.13.

EXAMPLE 11 1-Cyclohexy1-3-f4-[2-(4-methyl5-thiazolccarboxamido)- ethyllbenzenesu fonyl}urea 50 The procedure described 11'! Example I was repeated Sodium citgate Alginic aci except that I,1-diphenyl-3-(bicycle[2.2.l]hept-5-enpnlyvinylpyrmlidonc l0 2-yl-endo-methyl)urea was the reagent of choice em- Magnesium stearate 5 ployed in lieu of cyclohexyl isocyanate, on the same molar basis as before. In this particular case, the corresponding final product obtained was l-(bicyclo- [2.2.1]hept-5-en-2-yl-endo-methyl)-3-{4-[2-(4- methyl-5-thiazolecarboxamido)ethy1]benzenesulfonyllurea, m.p. I53-l 55C.

Anal. Calcd. for C 5H N O S Found:

EXAMPLE III The procedure described in Example I is repeated except that cyclopentyl isocyanate' is the reagent of 40 choice employed in lieu of cyclohexyl isocyanate, on

the same molar basis as before. In this particular case;

EXAMPLE IV The sodium salt of 1-cyclohexyl-3-{4-[2-(4-methyl- S-thiazolecarboxamido)ethyl]benzenesu1fonyl} urea is prepared by dissolving said compound in anhydrous methanol and then adding said solution to another methanolic solution which contains an equivalent amount in moles of sodium methoxide. Upon subsequent evaporation of the solvent therefrom via freezedrying, there is obtained the desired alkali metal salt in the form of an amorphous solid powder which is freely soluble in water.

In like manner, the potassium and lithium salts are also similarly prepared. as are the alkali metal salts of the other benzenesulfonylureas of this invention which are reported in the previous examples.

ingredient, respectively, by merely using the appropriate amount of the benzenesulfonylurea in each case.

EXAMPLE VII A dry solid pharmaceutical composition is prepared by combining the following materials together in the proportions by weight indicated below:

l-(Bicyclo[2.2.l Ihept-S-en-Z-yl-endo-methyl)-3- {4-[2-(4-methyl-5-thiazolecarboxamido)ethyllbenzencsulfonyl}urea '50 Calcium carbonate 20 Polyethylene glycol, average molecular weight. 4000 30 The dried solid mixture so prepared is then thoroughly agitated so as to obtain a powdered product that is completely uniform in every respect. Soft elastic and hard-filled gelatin capsule containing this pharmaceutical composition are then prepared, employing a sufficient quantity of material in each instance so as to provide each capsule with mg. of the active ingredient.

EXAMPLE VIII The benzenesulfonylurea products of EXAMPLES H] were tested for hypoglycemic activity in groups of six male albino rats (each weighing approximately -240 g.) of the Sprague-Dawley strain. No anesthetic was used in this study. The rats were fasted for approximately 18-24 hours prior to administration. a blood sample was then taken from the tail vein of each animal and the test compound was administered intraperitoneally (while in solution as the sodium salt in 0.9% saline) at dose levels of 5.0, 1.0 and 0.5 mg./kg., respectively. Additional blood samples were then taken Hypoglyccmic Activity (Maxf/z Fall) Sulfonylurca 0.5mg./kg. l.()mg./kg. 5.0mg./kg.

Prod. a EX. 1 I7 41 43 Prod. of Ex. ll ll 39 43 What is claimed is:

l. A sulfonylurea compound selected from the group consisting of benzenesulfonylureas of the formula:

l 1 .11 1 b AONIIC ZCIIZQ SO NIILONIIR and the base salts thereof with pharmacologically acceptable cations. where R is bicyclo[2.2.1]hept-5-en- 2-yl-endo-methyl or seven carbon atoms.

2. A compound as cycloalkyl having from five to claimed in claim I wherein R is bicyclo[2.2.l ]hept-5-en-2yl-endo-methyl.

3. A compound as claimed in claim I where R is cyclohexyl.

S-thiazolecarboxamid 

1. A SULFONYLUREA COMPOUND SELECTED FROM THE GROUP CONSISTING OF BENZENESULFONYLUREAS OF THE FORMULA:
 2. A compound as claimed in claim 1 wherein R is bicyclo(2.2.1)hept-5-en-2-yl-endo-methyl.
 3. A compound as claimed in claim 1 wherein R is cyclohexyl.
 4. 1-Cyclohexyl-3-(4-(2-(4-methyl-5thiazolecarboxamido)-ethyl) benzenesulfonyl)urea. 